By Prabhat Prakash and Abhishek Bhatia
New Delhi: Amyloidosis (am-uh-loi-DO-sis), as difficult as it may sound, is a very rare disease that doubles down on serious complications. Patients with amyloidosis tend to witness changes in their body with the extracellular tissue deposition of fibrils, insoluble polymers comprised of low molecular weight protein subunits, typically in the range of 5-25 kilodaltons (kD). The death of Former Pakistan President, Parvez Musharraf, has brought amyloidosis under the microscopic vision of the global healthcare industry.
Amyloidosis is a rare disease that affects nearly 4,000 people in the US every year. The death of Musharraf due to the disease took the internet by storm, and the very term ‘amyloidosis’ has been searched 100x more in the last week on the Google Trends chart than it has in the past decade or so. The spike in the search results and curiosities among netizens led to ETHealthworld diving deeper into the issue at hand, speaking to a series of medical practitioners with a vast experience base to gain insight into the intricacies associated with amyloidosis.
The tale of amyloid protein
Dr Shobha Subramanian Itolikar, Consultant Internal Medicine, Fortis Hospital Mulund, explained amyloidosis in great detail. She says, “Firstly, it is an abnormal protein, meaning it’s not normally produced by our body. Amyloid does not exist in a normal human body, at least not in youngsters. It is amorphous and structurally different from the proteins that are found in the body. It is insoluble since the structure is different, the body makes illicit reactions when this amyloid protein is produced. It is a multisystem disease and can affect any organ in the body, right from the skin to the tongue.”
Dr Itolikar continues, “Usually, the patients can have only tongue involvement or spots on the skin due to amyloidosis. It becomes a little bit dangerous for the patients when it starts involving organs. The vital organs in the body are the brain, heart, liver, and kidney. When they start getting affected, that is when the possibility of amyloidosis comes in.”
One of the most propped-up questions stamped on social media walls was whether people with higher protein consumption develop such disorders. Dr Subhendu Mohanty, Interventional Cardiologist, Sharda Hospital, Noida, does not find this reasonable.
Debunking the theory doing the rounds on social media, Dr Mohanty says, “It is not related to the protein intake; it is more related to the disease process. It is not dependent on protein intake. It is nothing like saying that if we take more protein, more amyloid will be formed. The amyloids are formed due to abnormal protein synthesis inside the body. Genetically speaking, it is a predisposition for some people to make amyloid protein. Those amyloid proteins will be made regardless of whether we take more or less protein.”
Experts believe these kinds of proteins are not supposed to be formed inside the body. Even if they form, the body removes them. Amalyoid protein gets deposited in various organs due to a protein problem, inadequate clearance by the body, or excessive production. The most common places where they get deposited are the heart, kidney, and nerves.
According to Dr Mohanty, amyloid protein is a very rare protein. He adds, “There are several varieties of amyloidosis, but the most common one is related to multiple myeloma. In those cases, unless the treatment is focused on multiple myeloma per se, the restriction of protein is not going to help in decreasing the amyloidosis. One has to treat the primary cause.”
Amyloid proteins cause organ failure
When asked about how the piling of amyloid proteins affects the functioning of organs, Dr Sudhir Kumar, Senior Consultant Neurologist, Apollo Hospitals, Jubilee Hills, Hyderabad, said, “The heart is affected in about 50 per cent of cases of amyloidosis, leading to heart failure. Symptoms include fatigue, breathlessness, and swelling of feet. The liver gets affected in 15-25 per cent of cases and leads to jaundice, distension of the abdomen (ascites) and swelling of feet. Involvement of nerves occurs in 15-20 per cent of cases of amyloidosis and causes numbness and tingling of the feet, a drop in blood pressure upon standing, and impotence. In 30 per cent of patients, three or more organs are affected.”
Talking about the disease’s effect on the kidney, Dr Puneet Bhuwania, Consultant Nephrologist and Kidney Transplant Physician, Wockhardt Hospitals, Mira Road, said, “The deposition causes protein leakage in the urine and, if not cleared, can lead to complete kidney failure. A person also tends to develop swelling, which is difficult to resolve, and coupled with water collection in the lungs, leads to breathing difficulty again.”
Life expectancy after diagnosis
The Genetic and Rare Diseases Information Centre estimates that persons with familial ATTR amyloidosis live for 7-12 years on average after receiving their diagnosis. People with wild-type ATTR amyloidosis have an average survival time of four years after diagnosis.
Dr Ameet Mandot, HOD – Clinical Lead Adult Hepatology and Liver transplant, Global Hospitals Parel says, “Patients with AL amyloidosis on dialysis had a mean survival of 39 months, while median survival in patients with hepatic amyloidosis was nine months.”
Highlighting the fact that average life expectancy after diagnosis has been steadily increasing over the past three decades, Dr Kumar said, “It has increased from 1.4 years in the 1990s to 4.6 years in the last decade. The median life expectancy for patients who develop heart failure is about six months. Long-term survival of 10-20 years may be seen in one out of five patients who are treated with high-dose melphalan/stem cell transplantation.”
Complications and treatments
Although there is no full-proof treatment mechanism available to cure amyloidosis, several treatments for transthyretin amyloidosis have recently been approved by the US FDA. When asked about some of the treatment options available in India and where they fell in terms of expenses, Dr Kumar pointed out, “The cost of treatment is on the higher side and may be unaffordable for most sections of people in India (those without public or private insurance coverage).”
“Tafamidis is an FDA-approved oral medication for treating cardiomyopathy and peripheral neuropathy due to transthyretin amyloidosis (ATTR). Before this drug approval, the only treatment option was heart transplantation. This treatment option is available in India. Other treatment options for light chain amyloidosis, such as high-dose melphalan and stem cell transplantation, are also available in India,” he added.
Dr Mandot points out the complications in the course of treatment, “Complications are related to drugs used, like colchicine used for amyloidosis, which can cause familial Mediterranean fever, and azathioprine, chlorambucil, methotrexate, and cyclophosphamide used for secondary amyloidosis. Venetoclax used for hepatic amyloidosis has complications like oedema, hyperglycemia, and hyperkalemia.”
Complications are mostly related to disease progression. Dr Kumar said, “About one-third of patients develop heart failure and get severe breathlessness. They are unable to lie down flat due to breathlessness (orthopnea) and need to spend the entire night in a sitting position. If the gut is affected, there is malabsorption, leading to diarrhoea and weight loss.”
Diagnosis challenges in India
Patients in the US wait an average of 7.6 years for an accurate diagnosis of a rare disease, while patients in the UK wait an average of 5.6 years. According to a recent study (four primary care physicians and four specialists), up to eight doctors are involved. Additionally, it’s usual to receive two to three incorrect diagnoses before receiving the correct one.
Emphasising amyloidosis is not immediately life-threatening, Dr Itolikar says, “Patients as well as doctors don’t think of the amyloidosis diagnosis right in the beginning. Because the diagnosis per se is an invasive test, one has to take facts from the abdominal wall and then demonstrate. So nobody would think of a rare diagnosis; a common diagnosis is what we always think of. The average curve is that the patient goes to multiple doctors only when a complication related to organ failure arrives. The patient would be very lucky if the amyloidosis is diagnosed early in the course.”
Dr Mohanty mentions the real-time challenges of diagnosing a disease like amyloidosis. “If you see the overall medical infrastructure itself, it is quite weak. If we think of tertiary care centres in Delhi, the government’s healthcare infrastructure is not as good. If we go to the periphery, there are hardly any large institutes that do all types of major lab investigations; because of this, we have to rely on private labs. This makes the diagnosis itself very costly, and if we approach the government labs, it takes a very long time. So, the serum electrophoresis is the first important investigation that we need to suspect and diagnose amyloidosis.”
“Even after going through serum electrophoresis, one may get the impression (around 80 per cent) that amyloidosis is suspected. But confirmation always comes via biopsy, and in any case, to label the disease, a biopsy is required. In India, going by our population, we might have many more cases of amyloidosis than in any other country. It is because of these diagnostic challenges that we are not able to diagnose these cases as frequently as any other well-equipped country,” Dr Mohanty added.
Medical practitioners generally consider amyloidosis a secondary disease. According to the Mayo Clinic, people diagnosed with amyloidosis are mostly aged between 60-70 years of age, which, in other words, means that old people are most susceptible to this disease. Patients already suffering from a chronic infectious or inflammatory disease such as rheumatoid arthritis (RA) or inflammatory bowel disease (IBS) have higher chances of amyloidosis development alongside the existing condition. People with a family history can develop familial amyloidosis.
“Post-COVID-19 pandemic, people are becoming more aware of their health conditions. There is optimism about diagnosing this disease at an early stage. Once we diagnose diseases at an early stage we can start treatment for the primary problem so that secondary issues don’t arise later on. As the diseases become very late in their course, you need a greater number of investigations, and the treatment also becomes costly,” Dr Bhuwania said.
National policy on rare diseases and data crunch
The Union Ministry of Health and Family Welfare (MoHFW) revised the National Policy for Rare Diseases (NPRD) in 2021 due to serious implementation challenges in its previous avatar. The policy specifically mentions the lack of data on rare diseases as a major challenge for India’s health sector. The Department of Health Research (DHR), with ICMR as a member, was entrusted with the responsibility of setting up a National Consortium for Research and Development on Therapeutics for Rare Diseases, “to include research and development, technology transfer, and indigenisation of therapeutics for rare diseases.”
The consortium’s official website mentions 450 rare diseases identified in India, a very low number in contrast to the global benchmarks. Of all the ICMR-funded research projects underway on rare diseases, only two were assigned to amalydosis.
Dr Bhuwania underlines that this problem of data crunching is aligned with the larger problem of the doctor-patient ratio in India. He says, “We have too many patients, and most doctors are busy treating patients. So collecting data becomes challenging because we don’t have time to even make a note of a particular disease. Since we are a developing nation, our poverty levels are high. These kinds of diseases are seen more in socio-economically marginalised sections of the population.”
“People with these vulnerabilities tend to end up at government hospitals, and it takes invasive testing to diagnose such diseases, which in itself is not an easy process. The doctor-patient ratio in our country is very skewed, and that is the opposite in the developed countries, which gives them time as an added advantage to do research,” he concludes.